Transglutaminases form isodipeptide crosslinks between acceptor amide groups of glutaminyl residues and donor epsilon-NH2 groups of lysines. In the epidermis, and other stratified squamous epithelial tissues, these enzymes are thought to be involved in the crosslinking of putative protein components to form the insoluble cell envelope. Using molecular biology approaches, we have found that there are 3 different transglutaminase activities in normal human and mouse epidermis. These are known as the K, C and E enzymes. Work is in progress to isolate and characterize cDNA and genomic clones encoding each of these. The aim of these studies is to determine the likely functions of these different activities in normal and abnormally keratinizing epidermis.